Cigarette smoking is incontrovertibly the major risk factor for lung cancer. However most environmental carcinogens, including those in tobacco smoke, require metabolic activation by cytochrome P450 enzymes in order to exert their deleterious effects. Conversely, endogenous detoxication enzymes, such as glutathione S-transerases, can react with these activated intermediates. Polymorphisms exist in the genes responsible for both activation and inactivation and may contribute to interindividual differences in susceptibility to lung carcinogens. The possible association between biologically relevant polymorphisms of carcinogens metabolism enzymes and lung cancer risk is being studied in two different study populations. The first is a case-control study of African-Americans and Caucasians in Los Angeles County. Subject enrollment (356 cases and 731 control subjects) was completed by the principal investigator while she was a faculty member at University of Southern California. The second population is a cohort study of 18,000 men in Shanghai. To date we have examine the polymorphisms of the following genes in the Los Angeles study and published results: GSTM1, CYP1A1, CYP2E1, CYP2C9, CYP2D6. Laboratory analyses are underway for CYP2A6, microsomal epoxide hydrolase and additional polymorphisms of CYP1A1 and CYP2C9. As new polymorphisms are described with biological relevance to lung cancer, we will be able to examine them in this study. Future work will also focus on tumor markers using blocks collected for cases. We have followed up an interesting finding of an association primarily seen among lighter smokers for the GSTM1 null genotype using DNA samples extracted from serum from the Shanghai cohort, a group with a large proportion of light smokers. We intend to examine relevant polymorphisms which are prevalent among Chinese subjects in this cohort in the future.